The incidence of cocaine-related sudden deaths has reached epidemic proportions in many metropolitan areas around the United States. Widespread cocaine abuse is associated with significant neuropsychiatric and from 1978 - 1985 has revealed a number of important findings regarding the temporal trends and risk factors surrounding cocaine-related sudden death. The epidemiological findings indicate that in Dade County only 6 to 11% of the cases had significant underlying coronary artery disease or ventricular hypertrophy, suggesting that these risk factors may account for only a subgroup of the cocaine-related deaths. In addition, polydrug abuse does not appear to be a significant risk factor in Dade County. High dose cocaine toxicity is associated with seizures. However, the percentage of cocaine-related deaths with seizures has declined during the epidemic. This pattern is consistent with toxicology findings which demonstrate that median plasma concentration of cocaine associated with sudden death also appear to be declining annually. In contrast, an increased incidence of preterminal excited delirium and sudden death has been reported which closely follows the epidemic curve for cocaine-related deaths in Dade County. These observations suggest that the causes of cocaine-related death in decedents with comparatively low concentrations of blood cocaine may be different from the high dose toxicity group. The precise pathophysiological mechanisms leading to cocaine-related sudden death are not well defined and, at present, all known mechanisms fail to explain why cocaine abuse may have divergent effects on the heart. Our hypothesis is that cocaine abuse results in abnormal neuronal activity in limbic and brainstem centers comprising the neural substrates which mediate central autonomic functions. Abnormal neurochemical transmission in these pathways may, in addition to the direct cardiotoxic effects of cocaine, lead to the pathogenesis of cocaine-related sudden death. The present proposal seeks funds for systematic post mortem studies of the chemo- and pathoarchitecture in brains from victims of cocaine-related death. Using rigorous inclusion criteria for cocaine exposure, the cases selected for neuroanatomical studies will be classified into the following subgroups : high dose toxicity (seizures); low dose toxicity without significant underlying cardiac pathology; and cocaine-related death in subjects exhibiting preterminal excited delirium. We propose to characterize post mortem neurochemical alteration in brains from victims of cocaine-related sudden death using in vitro autoradiography on whole-brain sections. The distribution and status of norepinephrine and dopamine terminals will be visualized in whole-brain sections by receptor subtypes and sigma receptors will be correlated with limbic and medullary pathoarchitecture and whenever possible with the pattern of use and drug and metabolite levels in plasma and brains. The proposed anatomical studies may disclose the toxic effects of an neural sites for the action of cocaine in the human brain. These studies may provide a basis for pharmacologically targeting multiple, interactive dysfunctions in the brain in order to halt cocaine abuse in chronic users.